Air pollution and Dementia: Exploring genetic, cardiovascular, and epigenetic moderators and mechanisms

空气污染和痴呆症：探索遗传、心血管和表观遗传调节因素和机制

• 批准号: 2604990
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2604990
• 关键词: Air; pollution; Dementia; Exploring; genetic

Background: Dementia is a major, growing public health priority. A person's genetic makeup can place them at higher risk of dementia, but there are also important environmental predictors that can increase risk. Air pollution is one of these, with evidence converging worldwide on the negative effects of pollution on brain health. These population studies have been extremely large, sampling millions of people, but they ignore a person's genetic predisposition. It is possible that pollutants interact with a person's genetic risk of dementia: greater air pollution might increase one's genetic risk, and one's genetic makeup can imply greater susceptibility or resilience to environmental insults. Air pollution also predicts cardiovascular disease (CVD), which in turn predicts dementia, and it is plausible that CVD itself and/or CVD risk factors mediate the observed association between pollutants and dementia, as indicated in prior work. It is also possible that air pollution affects brain health through altering of biological mechanisms such as accelerated telomere (nucleotides that protect the end of chromosomes) shortening and altered DNA methylation (which can change gene expression), both of which are strongly associated with ageing. Aims: The overarching aim of the project is to study the association between air pollution exposure across the lifespan and risk of dementia/cognitive decline. The aims include : 1) quantify the effects of gene by environment (air pollution) interaction on dementia. This will be done by a) applying classical twin design to data from the Swedish Twin Registry (STR), modelling gene by environment interactions to study whether genetic and environmental variance in dementia differ by levels of exposure to air pollution, and b) modelling a polygenic risk score for dementia in interaction with air pollution in the Lothian Birth Cohorts (LBCs), UK Biobank and STR, to specifically model interaction between air pollution and genetic risk of dementia on dementia status (UK Biobank, STR) and cognitive decline (LBCs where dementia analysis will be less powerful). 2) test whether air pollutants are causally related to dementia. This will be tested using a discordant MZ co-twin control design in the STR (N=1,214 pairs). In this design, MZ twins are perfectly matched for their genes and early environments, enabling comparison of their environmental exposure in adulthood in relation to their dementia status. A causal model would be supported if the twin with greater pollution exposure is the dementia case. 3) test if CVD mediates the effect of air pollutants on dementia. This will be examined by incorporating diagnoses of CVD in mediation models of air pollution and dementia in the LBCs and the STR while accounting for genetic risk of CVD and dementia. 4) test whether increased air pollutant exposure (over the lifetime in the LBCs and in the STR) is related to shorter telomere length and to methylation probes across the genome, and if so, whether these mediate the relationship between the air pollutant exposure and dementia. Uniquely, methylation data are available longitudinally (up to 20 years), so that we can also link them with longitudinal measures of air pollution.

背景：痴呆症是一个重要的、日益增长的公共卫生优先事项。一个人的基因构成会使他们面临更高的痴呆症风险，但也有重要的环境预测因素会增加风险。空气污染就是其中之一，全世界都有证据表明污染对大脑健康的负面影响。这些人口研究规模非常大，对数百万人进行了抽样，但它们忽略了一个人的遗传易感性。污染物可能会与一个人患痴呆症的遗传风险相互作用：更大的空气污染可能会增加一个人的遗传风险，一个人的基因构成可能意味着对环境侮辱的更大敏感性或更强的韧性。空气污染还预测心血管疾病(CVD)，而心血管疾病又预测痴呆症，正如先前的工作所表明的那样，CVD本身和/或CVD风险因素可能中介了污染物和痴呆症之间的观察到的关联。空气污染也可能通过改变生物机制来影响大脑健康，如加速端粒(保护染色体末端的核苷酸)缩短和DNA甲基化改变(这可以改变基因表达)，这两者都与衰老密切相关。目的：该项目的首要目标是研究终生空气污染暴露与痴呆症/认知能力下降风险之间的关系。其目的包括：1)量化基因与环境(空气污染)的交互作用对痴呆的影响。这将通过a)将经典的双胞胎设计应用于瑞典双胞胎登记处(STR)的数据，对不同环境的基因交互作用进行建模，以研究痴呆症的遗传和环境差异是否因暴露于空气污染的水平而不同，以及b)在洛锡安出生队列(LBC)、英国生物库(UK Biobank)和STR中，在与空气污染的交互作用中建立痴呆症的多基因风险分数，以具体模拟空气污染与痴呆症遗传风险之间的交互作用，从而影响痴呆症状态(英国生物库，STR)和认知下降(LBC，在LBC中，痴呆症分析将不那么强大)。2)测试空气污染物是否与痴呆症有因果关系。这将在STR(N=1,214对)中使用不协调的MZ同生双胞胎设计进行测试。在这项设计中，MZ双胞胎的基因和早期环境完全匹配，可以比较他们成年后暴露在环境中的情况与他们的痴呆症状态的关系。如果双胞胎中接触污染较多的那个是痴呆症，那么因果模型就会得到支持。3)检测CVD是否介导了空气污染物对痴呆的影响。这将通过将心血管疾病的诊断纳入LBC和STR的空气污染和痴呆症的中介模型中进行检查，同时考虑心血管疾病和痴呆症的遗传风险。4)测试空气污染物暴露的增加(在LBC和STR的一生中)是否与较短的端粒长度和整个基因组的甲基化探针有关，如果是，这些是否调节了空气污染物暴露和痴呆症之间的关系。独一无二的是，甲基化数据是纵向的(长达20年)，因此我们还可以将它们与空气污染的纵向测量联系起来。